Methods for relieving bronchospasm with prostaglandin a compounds

ABSTRACT

MEMBERS OF THE PROSTAGLANDIN -A SERIES, 19-HYDROXYLATED DERIVATIVES THEREOF, THEIR ESTERS, ALKALI METAL SALTS, AND AMINE SALTS ARE EMPLOYED IN COMPOSITIONS AND METHODS FOR RELIEVING BRONCHIAL SPASM AND FACILITATING BREATHING IN WARM BLOODED ANIMALS. ADMINISTRATION BY THE ORAL INHALATION ROUTE IS PARTICULARLY EFFECTIVE.

United States Patent 01 fice 3,755,599 Patented Aug. 28, 1973 3,755,599 METHODS FOR RELIEVING BRONCHOSPASM WITH PROSTAGLANDIN-A COMPOUNDS Marvin E. Rosenthale, Havertown, and Donald P. Strike,

Rosemont, Pa., assignors to American Home Products Corporation, New York, N.Y.

No Drawing. Filed Jan. 3, 1972, Set. No. 215,209 Int. Cl. A61k 27/00 US. Cl. 424-305 4 Claims ABSTRACT OF THE DISCLOSURE Members of the prostaglandin-A series, l9-hydroxylated derivatives thereof, their esters, alkali metal salts, and amine salts are employed in compositions and methods for relieving bronchial spasm and facilitating breathing in warm blooded animals. Administration by the oral inhalation route is particularly effective.

BACKGROUND OF THE INVENTION A number of compounds in a variety of combinations and dosage forms are currently available as bronchodilators, i.e.: substance able to relax the smooth muscle of the bronchial tree and thus control spasm and facilitate breathing in conditions affecting animals, such as bronchial asthma, bronchitis, bronchiectasis, pneumonia, emphysema, and the like. All of the bronchodilator preparations incorporate one or more of three basic types of compounds: (a) sympathomimetic (adrenergic) agents, (b) xanthine derivatives and (c) corticosteroids. These agents are frequently used in combination with anti-tussives, expectorants, mucolytics, and the like.

The sympathomimetic agents most often used are epineph'rine, isoproterenol, phenylephr-ine and ephiedrine. These adrenergic agents are most powerful and useful drugs in the relief of severe asthmatic spasm (status asthmaticus); however, as with other dilators they have untoward side efiects. Some of the more undesirable of these are stimulation of the cardiovascular and central nervous system, hyperglycemic and tolerance (tachyphylaxis), which greatly reduces the effectiveness of these drugs.

The two xanthine derivatives most widely used are theophylline and aminophylline. Some of the problems associated with therapy with these drugs include variable oral absorption, cardiovascular effects and inability to achieve adequate levels without gastric irritation.

Many cases of asthma and status asthmaticus refractory to usual treatment methods are now controlled by the corticosteroids. However, long term treatment of asthma with steroids involves the risk of sodium retention, hypertension, ulcers, calcium loss from osseous structures and other well known side effects.

Thus, the agents presently avaliable to the physician have a number of problems associated with their use, including toxicity, low activity (especially in the xanthines), adverse effect on the cardiovascular system (especially in the sympathomimetics) and fluid retention or edema (with the corticosteroids). Thus, a definite need exists for means employing effective and well-tolerated bronchodilating agents.

The difliculty in finding such agents is well known to those skilled in the art. It is a matter of common knowledge and experience, for example, that many compounds that relax smooth muscles are not bronchodilators by all common routes of administration (and especially by the aerosol route of administration). For example, for some obscure reason, ephedrine is a smooth muscle relaxant and is an orally active bronchodilator, but not by aerosol, epinephrine, also a smooth muscle relaxant, is used by aerosol but not orally. And aminophylline, a

drug which can relax bronchial smooth muscle in vitro or by injection in vivo is inactive as a bronchodilator aerosol. In view of this, although it is manifestly desirable, it has proven quite difiicult to find means which, even though characterized by smooth muscle relaxing activity, provide bronchodilation by injection, by oral administration and by administration via the aerosol route, possess high levels of activity, and are non-toxic.

In Belgian Pats. 711,025 and 736,977 there are disclosed means for accomplishing such salutory bronchodilating and bronchial spasm reducing effects by use of preparations containing certain prostaglandin compounds. The prostaglandin compounds there described as being thus useful are members of the prostaglandin-E and prostaglandin-F, series, and possess the following functions in the cyclopentyl moiety of the prostanoic acid skeleton:

The PGE and PGF, compounds possess in common saturated cyclopentyl moieties which contain a-hydroxymethylene groups at position-3.

The present invention provides methods and compositions for relieving bronchial spasm and facilitating breathing in warm blooded animals, which methods and compositions employ certain prostaglandin-A (PGA) compounds. Thesc PGA compounds possess in common the cyclopentenyl function:

PGA

SUMMARY OF THE INVENTION wherein (i) X, Y and Z are single bonds, R is hydrogen or lower alkyl carbonyl, and R is hydrogen;

(ii) X is a trans-double bond, Y and Z are single bonds,

R is hydrogen or lower alkyl carbonyl and R is hydrogen;

(iii) X is a trans-double bond, Y and Z are single bonds,

R is hydrogen and R is hydroxyl;

(iv) X is a trans-double bond, Y is a cis-double bond, Z

is a single bond, R is hydrogen or lower alkyl carbonyl and R is hydrogen;

(v) X is a trans-double bond, Y is a sis-double bond, Z is a single bond, R is hydrogen and R is hydroxyl;

(vi) X is a trans-double bond, Y and Z are cis-double bonds, R is hydrogen or lower alkyl carbonyl and R is hydrogen;

and R is hydrogen, alkyl of from 1 up to about 6 carbon atoms, alkali metal, or a pharmacologically acceptable cation derived from ammonia or a basic amine; and

(b) A pharmacologically acceptable carrier.

The invention sought to be patented in its composition aspect resides in the concept of a bronchodilating and bronchial spasm reducing composition formulated for inhalation therapy from a nebulizer such that each dose comprises:

(a) A bronchodilating and bronchial spasm reducing amount of a compound of the formula.

(i) X, Y and Z are single bonds, R is hydrogen or lower alkyl carbonyl, and R is hydrogen;

(ii) X is a trans-double bond, Y and Z are single bonds,

R is hydrogen or lower alkyl carbonyl and R is hydrogen;

(iii) X is a trans-double bond, Y and Z are single bonds,

R is hydrogen and R is hydroxyl;

(iv) X is a trans-double bond, Y is a cis-double bond, Z is a single bond, R is hydrogen or lower alkyl carbonyl and R is hydrogen;

(v) X is a trans-double bond, Y is a cis-double bond, Z

is a single bond, R is hydrogen and R is hydroxyl; (vi) X is a trans-double bond, Y and Z are cis-double bonds, R is hydrogen or lower alkyl carbonal and R is hydrogen;

and R is hydrogen, alkyl of from 1 up to about 6 carbon atoms, alkali metal, or a pharmacologically acceptable cation derived from ammonia or a basic amine; and

(b) A pharmacologically acceptable inhalation carrier, in an amount sufiicient to provide a composition administerable by the oral inhalation route.

DESCRIPTION OF THE PREFERRED EMBODIMENTS All of the compounds of Formula I employed in the methods and compositions of this invention are either known in the art or can be conveniently prepared by methods known in the art. Compounds of Formulae I(ii), I(iii), I(iv), and I(v), Where R and R are both hydrogen are the naturally occurring prostaglandin compounds PGA and PGAg and their naturally occurring 19-hydroxy derivatives, and are described, for example, in Prostaglandins, Proceedings of the Second Nobel Symposium, Interscience Publishers, 1966, pp. 21 et seq. The compound of Formula I(i) where R and R are both hydrogen is dihydrO-PGA and may be prepared from the naturally occurring compound PGE by known methods, for example as described in South African Pat. 66/ 3,600. The compound of Formula I(vi) where R and R are both hydrogen is the compound PGA and may be prepared from the naturally occurring compound PGE by known methods, such as that described in the aforementioned South African patent.

The compounds of Formula I wherein R is alkyl are prepared by standard methods, such as for example, by

treating a solution of the free acids with diazomethane or other appropriate diazohydrocarbons, such as diazoethane, l-diazo-Z-ethylpentane, and the like. The alkali metal carboxylates of the invention can be prepared by mixing stoichiometrically equivalent amounts of the free acids of Formula I, preferably in aqueous solution, with solutions of alkali metal bases, such as sodium, potassium, and lithim hydroxides or carbonates, and the like, then freeze drying the mixture to leave the product as a residue. The amine salts are prepare by mixing the free acids, preferably in solution, with a solution of the appropriate amine, in water, isopropanol, or the like, and freeze drying the mixture to leave the product as a residue. The compounds of Formula I wherein R is lower alkyl carbonyl may be prepared by standard acylation procedures such as, for example, treating the corresponding compound wherein R is hydrogen with the appropriate carboxylic acid anhydride in the presence of pyridine.

The term alkyl of from about 1 to about 6 carbon atoms when used herein and in the appended claims includes straight and branched chain hydrocarbon radicals, illustrative members of which are methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, n-hexyl, 3-methylpentyl, 2,3-dimethylbutyl, and the like. Alkali metal includes, for example, sodium, potassium, lithium, and the like. A "pharmacologically-acceptable cation derived from ammonia or a basic amine contemplates the positively charged ammonium ion and analogous ions derived from organic nitrogenous bases strong enough to form such cations. Bases useful for the purpose of forming pharmacologically-acceptable non-toxic addition salts of such compounds containing free carboxyl groups form a class whose limits are readily understood by those skilled in the art. Merely for illustration, they can be said to comprise, in cationic form, those of the formula:

wherein R R and R independently, are hydrogen, alkyl of from about 1 to about 6 carbon atoms, cycloalkyl of from about 3 to about 6 carbon atoms, monocarbocyclicaryl of about 6 carbon atoms, monocarbocyclicarylalkyl of from about 7 to about 11 carbon atoms, hydroxyal-kyl of from about 1 to about 3 carbon atoms, or monocarbocyclicarylhydroxyalkyl of from about 7 to about 15 carbon atoms or, when taken together with the nitrogen atom to which they are attached, any two of R R and R form part of a 5 to 6-membered heterocyclic ring containing carbon, hydrogen, oxygen, or nitrogen, said heterocyclic rings and said monocarbocyclicaryl groups being unsubstituted or monoor dialkyl substituted, said alkyl groups containing from about 1 to about 6 carbon atoms. Illustrative therefore of R groups comprising pharmacologically-acceptable cations derived from ammonia or a basic amino are ammonium, mono-, di, and trimethylammonium, mono-, diand triethylammoniurn, mono-, di-, and tripropylammoniurn (iso and normal), ethyldimethylammonium benzyldimethylammonium, cyclohexylammonium, benzylammonium, dibenzylammonium, piperidinium, morpholinium, pyrrolidinium, piperazinium, l-methylpiperidinium, 4-ethylmorpholnium, l-isopropylpyrrolidim'um, 1-4-dimethylpiperazinium, l-n-butylpiperidinium, 2-methylpiperidinium, 1-ethyl 2 methylpiperidinium, mono-, diand triethanolammonium, ethyldiethanolammonium, n-butylmonoethanolammonium, tris hydroxy(methyl)methylammonium, phenylmonoethanolammonium, and the like. The term lower alkyl carbonyl" when used herein and in the appended claims includes straight and branched chain carboxylic acyl groups of from 2 to about 7 carbon atoms, such as acetyl, propionyl, and the like.

In practicing the method of the invention, the instant compositions can be administered in a variety of dosage forms, the oral route being used primarily for maintes nance therapy while injectables tend to be more useful in acute emergency situations. Inhalation (aerosols and solution for nebulizers) is generally faster acting than other oral forms but slower than injectables and this method combines the advantages of maintenance and moderately-acute stage therapy in one dosage unit.

The daily dose requirements vary with the particular compositions being employed, the severity of the symptoms being presented, and the animal being treated. The dosage varies with the size of the animal. With large animals (about 70 kg. body weight), by the oral inhalation route, with for example a hand nebulizer or a pressurized aerosol dispenser the dose is from about micrograms to about 250 micrograms, and preferably from about 25 to about 75 micrograms, approximately every four hours, or as needed. By the oral ingestion route, the effective dose is from about 5 to about 50 mg., preferably from about 10 to about 25 mg. up to a total of about 100 mg. per day. By the intravenous route, the ordinarily effective dose is from about 100 micrograms to about 500 micrograms, preferably about 250 micrograms per day.

For unit dosages, the active ingredient can be compounded into any of the usual oral dosage forms including tablets, capsules and liquid preparations such as elixirs and suspensions containing various coloring, flavoring, stabilizing and fiavor masking substances. For compounding oral dosage forms the active ingredient can be diluted with various tableting materials such as starches of various types, calcium carbonate, lactose, sucrose and dicalcium phosphate to simplify the tableting and capsulating process. A minor proportion of magnesium stearate is useful as a lubricant. In all cases, of course, the proportion of the active ingredient in said composition will be sufiicient to impart bronchodilating activity thereto. This will range upward from about 0.000l% by weight of active ingredient in said composition.

For administration by the oral inhalation route with conventional nebulizers or by oxygen aerosolization it is convenient to provide the instant active ingredient in dilute aqueous solution, preferably at concentrations of about 1 part of medicament to from about 100 to 200 parts by weight of total solution. Entirely conventional additives may be employed to stabilize these solutions or to provide isotonic media, for example, sodium chloride, sodium citrate, citric acid, sodium bisulfite, and the like can be employed.

For administration as a self-propelled dosage unit for administering the active ingredient in aerosol form suitable for inhalation therapy the composition can comprise the active ingredient suspended in an inert propellant (such as a mixture of dichlorodifiuoromethane and dichlorotetrafluoroethane) together with a co-solvent, such as ethanol, flavoring materials and stabilizers. Instead of a co-solvent there can also be used a dispersing agent such as oleyl alcohol. Suitable means to employ the aerosol inhalation therapy technique are described fully in US. Pats. 2,868,691 and 3,095,355, for example.

The following non-limitative examples will further illustrate the invention.

EXAMPLE 1 Anesthetized (Dial-urethane) guinea pigs were artificially respired at a constant positive air pressure (Starling miniature pump) and changes in tidal air during inspiration were recorded, according to the method of Rosenthale et al., Int. Arch. Pharmacol', 172, 91 (1968). The bronchoconstrictor agent histamine was administered at doses of 1 to 6 meg/kg. depending on each animals sensitivity to this compound, and control responses to histamine were thus established. (Bronchloconstrictor agents raise the resistance of the lungs to inflation thereby decreasing the tidal air flow.) The prostaglandin compound was then administered intravenously in 0.06 M aqueous phosphate bufier and the degree of inhibition of bronchoconstriction was determined.

RESULTS Percent Dose, No. inhibition of Compound meg/kg. pigs histamine 2-(3-hydroxyocty1)-5-oxo-3-cyclopentene-l-heptanoie acid, ethylester, 10 2 54 acetate 2-(3-hydroxyoctyl)-5-oxo-3-cyclopen 2 1 19 tene-l-heptanoic acid 1 71 1 Maximum effect 1-3 minutes after drug.

EXAMPLE 2 RESULTS Percent inhibition of No. acetyl- Dose pigs choline 1 2 14 2 54 15 mcg 3 63 1 Maximum effect 1-2 minutes after drug.

EXAMPLE 3 The procedure of US. Pat. 2,868,691 is used to prepare the instant compositions in self-propelling dosage unit forms.

A suitable measured quantity of the medicament is mixed with, and dissolved in, a measured amount of the co-solvent. A stabilizer, if desired, is added. A measured quantity of the resulting solution is then introduced into an open container. The open container and its contents are then cooled, preferably to a temperature below the boiling point of the propellant to be employed. A temperature of 25 F. is usually satisfactory. A measured quantity of the liqui-fied propellant which also has been cooled below its boiling point is then introduced into the container and mixed with the solution already present. The quantities of the components introduced into the container are calculated to provide the desired concentration in each of the final compositions. Without permitting the temperature of the container and its contents to rise above the boiling point of the propellant, the container is sealed with a closure equipped with a suitable dispensing valve arrangement. Upon warming to room temperature the contents of the container are mixed by agitation of the container to insure complete solution of the medicament. The sealed container is then ready to dispense the composition and provide the medicament in aerosol form.

Nebulizing units each containing 15 ml. are filled according to the manipulative procedure described above with the following composition:

These packages when adjusted to deliver 300 single oral instalations provide a single dose of 75 micrograms. A single inhalation is administered to control an acute bronchial spasm. If necessary, after 1 or 2 minutes have elapsed, a second dose may be administered.

EXAMPLE 4 An injectable unit dosage composition is prepared by dissolving 100 mg. of 2-(3-hydroxyoctyl)-5-oxo-3-cyclopentene-l-heptanoic acid in 30 ml. of 0.2 M sodium phosphate buffer, pH 7.4 and is made up to 100 ml. with distilled water. This solution of medicament, containing 1 mg./ ml. of active ingredient (calculated as the free acid) is stored frozen at 20 C. until thawed for sterile filtration. After sterile filtration through a 0.45 micron filter, 1 ml. aliquots are filled aseptically into sterile ampules. The ampules are flame sealed and the contents are frozen and stored at 20 C. until needed.

EXAMPLE 5 A composition is prepared comprising 1 part of 7-[2- (3-hydroxyl-octenyl)-5-oxo-3-cyclopenten-l-yl] 5 heptenoic acid and 500 parts by weight of 0.06 M aqueous phosphate buffer. For administration to relieve bronchial spasm by oral inhalation with a hand nebulizer, in animals of from about 20 to about 80 kilograms body weight, 3 to 5 inhalations of the solution are used every four hours.

EXAMPLE 6 Tablets for oral use are prepared with the following formulations:

Milligrams 2-(3-hydroxyoctyl)-5-oxo-3-cyclopentene-lheptanoic acid, ethyl ester, acetate 10 Lactose 287 277 Magnesium stearate 3 3 The subject matter which the applicants regard as their invention is particularly pointed out and distincly claimed as follows:

1. A method of relieving bronchial spasm and facilitating breathing in Warm blooded animals which comprises administering by the oral inhalation route to a warm blooded animal in need thereof an amount sufiicient to relieve bronchial spasm and facilitate breathing in said Warm blooded animal of a composition comprising:

(a) a compound of the formula wherein (i) X, Y and Z are single bonds, R is hydrogen or lower alkyl carbonyl and R is hydrogen;

(ii) X is a trans-double bond, Y and Z are single bonds, R is hydrogen or lower alkyl carbonyl and R is hydrogen;

(iii) X is a trans-double bond, Y and Z are single bonds, R is hydrogen and R is hydroxyl;

(iv) X is a trans-double bond, Y is a cis-double bond, R is hydrogen or lower alkyl carbonyl and R is hydrogen;

(v) X is a trans-double bond, Y is a cis-double bond, Z is a single bond, R is hydrogen and R is hydroxyl;

(vi) X is a trans-double bond, Y and Z are cisdouble bonds, R is hydrogen or lower alkyl carbonyl and R is hydrogen;

and R is hydrogen, alkyl of from 1 up to about 6 carbon atoms, alkali metal, or a pharmacologically acceptable cation derived from ammonia or a basic amine; and

(b) a pharmacologically acceptable carrier.

2. A method as defined in claim 1 wherein said compound is 2-(3-hydroxyoctyl)-5-oxo-3-cyclopentene-1-heptanoic acid, ethyl ester, acetate.

3. A method as defined in claim 1 wherein said com pound is 2-(3-hydroxyoctyl)-5-oxo-3-cyclopentene-l-heptanoic acid.

4. A method as defined in claim 1 wherein said compound is 7- [2-(3-hydroxy-l-octenyl) -5-oxo-3-cyclopenten- 1-yl]-5-heptenoic acid.

References Cited Bergstrom, et al.Pharmacological Reviews, vol. 20 (1968), p. 27.

Horton, Physiological Reviews, vol. 49, No. 1, January 1969, p. 143.

Jackson et al.-The Physiologist, vol. 10 (1967), p. 212

SAM ROSEN, Primary Examiner US. Cl. X.R. 424318 

